Project Summary Severe obesity in adolescence continues to rise and has far reaching metabolic consequences. Childhood obesity is responsible for $14 billion of direct medical care costs annually. It is thus essential to prevent obesity and its complications, which are crippling a third of the youth in the U.S. today. Bariatric surgery, particularly vertical sleeve gastrectomy (VSG), is being increasingly used to treat severe obesity. Evaluating metabolic changes after VSG and the mechanisms leading to these changes may help identify less invasive therapeutic targets for this condition. There is a significant improvement in glycemic control following surgery, primarily because of significant weight loss and associated improvement in insulin resistance and pancreatic function. Improving pancreatic function (or beta cell function) is especially important in adolescents because (i) their beta cells are under higher stress from the added insulin resistance of puberty, and (ii) the replicative potential of beta cells decreases with age and hence the maximal ability to preserve beta cells is during younger ages. There are no data regarding the outcomes of VSG in adolescents to date. Hence, in this proposal we will characterize the acute and long term changes in beta cell function and its determinants following VSG in adolescents, 14-21 years old. Moreover, a recent quest for mechanisms underlying these metabolic improvements post surgery has revealed that changes in bile acid secretion and composition and associated changes in the gut microbiome may be novel pathways associated with improving glycemic control. This proposal will prospectively follow 60 obese adolescents (30 undergoing usual medical care and 30 undergoing VSG) for 24 months and evaluate changes in bile acids and fecal microbiome after VSG. If the study identifies specific bile acid or fecal microbiome changes that are associated with improved beta cell function, this could form the basis for a future interventional trial. The proposed study will utilize several complementary sub- specialties- endocrinology, gastroenterology and genetics. The principal investigator, Dr. Singhal, is an Instructor in Pediatrics at Harvard Medical School and Pediatric Endocrinologist at Massachusetts General Hospital. Her long-term goal is to be an independent clinical investigator in the field of pediatric obesity and metabolism. Her career development will be closely guided by her co-mentors, Drs Misra, Bredella, Patti and Fasano, who together provide the required expertise in metabolic evaluation of obesity, bile acid physiology and microbiome analysis. Execution of the proposed project will provide Dr. Singhal with hands-on training in metabolic and genomic assessments in obese adolescents and pave way for future collaborations. In addition, the career development plan incorporates completion of a Master's degree in Public Health. This mentored research award will provide Dr. Singhal with the additional training critical to her success as an independent investigator in pediatric obesity. Understanding the mechanisms of beta cell function improvement will lead to the design of subsequent interventional trials to optimize metabolic health in adolescents with obesity.